An attenuated monocyte-tropic clone of SIV (SIV/17E-C1) has properties which are unique to a live attenuated SIV vaccine. Infection with SIV/17E-C1 induces an early vigorous type-specific neutralizing antibody response which broadens during the first 7 months postinfection to include activity against SIV/DeltaB670, a heterologous primary isolate. The induction of protective immune responses coincides with the switch from type-specific to group-specific neutralizing antibody, and, at least in part, appears mediated by antibody since sera from protected monkeys passively protected 2 of 4 recipients. A nef-deleted variant of this monocyte-tropic clone, unlike the lymphocyte-tropic parent SIVmac239Deltanef, also induced detectable class I restricted CTL during the first 6 months postinfection. These unique properties are likely due to a unique gp120 conformation imposed by sequences which enable it to replicate in macrophages, and/or selective presentation to the immune system by the infected macrophage. We propose to further characterize the protective responses induced by SIV/17E infection, and to utilize this information to develop a subunit vaccine which can mimic these responses. The protection observed by intravenous challenge of SIV/17E infected monkeys will be extended to the infected cell, delivered intravenously and at the mucosal surface (Murphy-Corb). Protective antibody will be defined by passive protection studies with purified Ig, and with Ig fractions specific to conformation dependent and independent responses (provided by Montelaro). The epitopes responsible for the induction of protective immunity will be defined by determining function (ACC,ADCC,: neutralization, Clements,), binding properties, and mapping of both polyclonal Ig fractions and monoclonal antibodies derived from SIV/17E-infected monkeys (Robinson). Class I restricted CTL activity will be assessed to correlate these responses to protection. A purified recombinant subunit vaccine and DNA vaccines, alone, or in combination with cytokine expression vectors, and delivered either by direct injection or by the particle delivery system of Agracetus comprised of SIV/17E sequences will be employed to develop a noninfectious vaccine approach that mimics the protection observed with a live attenuated vaccine. The correlates of protection will be readily identified in these vaccines by the comprehensive technology provided by the 4 projects of this NCVDG. The optimal HIV vaccine strategy is one which is efficacious in both SIV (disease) and HIV (infection) model systems. Therefore, a working model for evaluating HIV glycoprotein vaccines will be established using constructs provided Aim 4. SIV/SHIV recombinants will be evaluated for their ability to serve as attenuated vaccines. A panel of SHIV constructs will be used to develop a polyvalent HIV gp120 vaccine testing system, and to extend efficacious SIV subunit vaccines developed in this NCVDG to HIV.